Nitric oxide (NO) is an important pleiotropic molecule mediating a wide range of physiological and pathophysiological processes. For example, it enhances activity of cyclooxygenase II (COX-II), which is responsible for the synthesis of the prostaglandins that mediate inflammation, pain, and fever (Liu, Q. et al., Carcinogenesis, 2003, Vol. 24, No. 4, 637-642). As another example, it also increases the expression of signal kinase MEKK1, which plays a key role in the NF-κB activation pathway (Chou F. P. et al., Toxicology and Applied Pharmacology, 2002, Vol. 181, No. 3: 203-206). Overproduction of NO has been implicated in various pathological processes, including septic shock, tissue damage following inflammation, cancer, and rheumatoid arthritis.
NO is produced from L-arginine and molecular oxygen by three distinct isoforms of nitric oxide synthase (NOS), i.e., neural NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Among the three isoforms, iNOS can be induced by endotoxins, cytokines (e.g., TNF-α), or transcriptional factors (e.g., NF-κB and AP1). Inhibiting expression or activity of iNOS is a major target for preventing and eliminating NO overproduction.